New route to alpha-tocopherol, alpha-tocopheryl alkanoates and precursors thereof

ABSTRACT

The present invention is concerned with a novel process for the manufacture of (E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytylphenyl esters and silyl ethers, precursors of α-tocopherol and α-tocopheryl alkanoates, by cross-metathesis reaction of 2-alkenyl-3,5,6-trimethylhydroquinone dialkanoates or 4-alkanoyloxy-2-alkenyl-3,5,6-trimethylphenyl silylethers with 2,6,10,14-tetramethylpentadecene or a phytol derivative, e.g. phytyl acetate, in the presence of a cross-metathesis catalyst. As the cross-metathesis catalyst especially ruthenium metal carbene complexes are suitable which possess (a) ruthenium metal center(s), have an electron count of 16 or 18 and are penta- or hexa-coordinated. A further object of the invention is a process for the manufacture of α-tocopherol and α-tocopheryl alkanoates comprising this reaction.

The present invention is concerned with a novel process for themanufacture of (E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytylphenyl estersand silyl ethers, precursors of α-tocopheryl alkanoates andα-tocopherol, by cross-metathesis reaction of2-alkenyl-3,5,6-trimethylhydroquinone dialkanoates or4-alkanoyloxy-2-alkenyl-3,5,6-trimethylphenyl silylethers with2,6,10,14-tetramethylpentadecene or a phytol derivative, e.g. phytylacetate, in the presence of a cross-metathesis catalyst. A furtherobject of the invention is a process for the manufacture of α-tocopherylalkanoates and α-tocopherol comprising this reaction step.

As is known, (all-rac)-α-tocopherol (or as it has mostly been denoted inthe prior art, “d,l-α-tocopherol”) is a diastereoisomeric mixture of2,5,7,8-tetramethyl-2-(4′,8′,12′-trimethyl-tridecyl)-6-chromanol(α-tocopherol), which is the most biologically active and industriallymost important member of the vitamin E group. Often the acetate oranother alkanoate of α-tocopherol is produced since it is more stableand more convenient to handle in contrast to α-tocopherol which islabile against oxidative conditions.

Many processes for the manufacture of “d,l-α-tocopherol” (referred to assuch in the literature reviewed hereinafter) and its acetate aredescribed in literature, of which some examples are discussed below.They all have in common that α-tocopherol or its acetate are produced bythe reaction of trimethylhydroquinone (TMHQ)/trimethylhydroquinoneacetate (TMHQA) with isophytol (IP), phytol (PH) or its derivatives inthe presence of a catalyst or catalyst system and in a solvent orsolvent system.

According to EP 0 100 471 e.g. the reaction of TMHQ with IP or PH iscarried out in the presence of a Lewis acid, e.g. ZnCl₂, BF₃ or AlCl₃, astrong acid, e.g. HCl, and an amine or an amine salt of a non-oxidizingprotic acid as the catalyst system.

EP-A 0 658 552 discloses a process for the preparation of α-tocopheroland derivatives thereof, wherein fluorosulfonates [M(RSO₃)₃], nitrates[M(NO₃)₃] and sulfates [M₂(SO₄)₃] are used as the catalysts with Mrepresenting a Sc, Y or lanthanide atom, and R representing fluorine, afluorinated lower alkyl or an optionally single or multiple fluorinatedaryl. The reaction is carried out in a solvent which is inert to thecatalyst and the starting materials, TMHQ and allyl alcohol derivativesor alkenyl alcohols, examples of the solvent being aromatichydrocarbons, linear and cyclic ethers, esters and chlorinatedhydrocarbons.

According to EP-B 0 694 541 a carbonate ester, a lower fatty acid esteror a mixed solvent of a non-polar solvent and a lower C₁₋₅-alcohol isused as solvent for the preparation of α-tocopherol starting with TMHQand (iso)phytol or phytol derivatives. As the catalyst a mineral acid, aLewis acid, an acidic ion exchange resin or a triflate, nitrate orsulfate of Sc, Y or a lanthanid element is used.

In the process of EP-A 1 180 517 TMHQ and IP or PH are reacted in thepresence of a bis-(perfluorinated hydrocarbyl sulphonyl)imide or a metalsalt thereof to obtain α-tocopherol. Solvents for this reaction arepolar organic solvents such as aliphatic and cyclic ketones, aliphaticand cyclic esters and carbonates, and non-polar organic solvents such asaliphatic and aromatic hydrocarbons or mixtures thereof.

The reaction of TMHQ/TMHQA with isophytol, phytol or an (iso)phytolderivative has the disadvantage of the formation of by-products such asphytadienes and benzofurans. The separation of these by-products fromα-tocopherol and its esters such as the acetate, respectively, is ratherdifficult.

The object of the present invention is to provide a process for themanufacture of (all-rac)α-tocopheryl alkanoates, which are stableagainst oxidative conditions, α-tocopherol, and precursors thereof,whereby the production of benzofurans/phytadienes is avoided.Furthermore the catalyst used should have no, or at least a muchreduced, corrosive action.

In one aspect the present invention is related to a process for themanufacture of compounds represented by the following formula III, socalled (E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytyl-phenyl ester(=(E/Z)-2-phytyl-3,5,6-trimethylhydroquinone dialkanoate) or(E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytyl-phenyl silyl ether,

wherein R¹ and R² are as defined below,by reacting

-   -   a) a compound represented by the following formula I, so-called        4-alkanoyloxy-2-alkenyl-3,5,6-trimethylphenyl ester        (=2-alkenyl-3,5,6-trimethylhydroquinone dialkanoate; if        R²═C₂₋₅-alkanoyloxy) or        4-alkanoyloxy-2-alkenyl-3,5,6-trimethylphenyl silyl ether (if        R²═OSiR⁶R⁷R⁸),        wherein R¹ is C₂₋₅-alkanoyloxy,

R² is C₂₋₅-alkanoyloxy or OSiR⁶R⁷R⁸, wherein R⁶, R⁷ and RB areindependently from each other C₁₋₆-alkyl or phenyl,

R³ and R⁴ are independently from each other H or C₁₋₅-alkyl, with theproviso that at least one of R³ and R⁴ is not H, with

-   -   b) a compound represented by the following formula II,        2,6,10,14-tetramethylpentadecene (if R⁵H) or a phytol derivative        (if R⁵═CH₂R⁹),

wherein R⁵ is H or CH₂R⁹, wherein R⁹ is formyloxy, C₂₋₅-alkanoyloxy,benzoyloxy, C₁₋₅-alkoxy or OSiR⁶R⁷R⁸ as defined above,

in the presence of a cross-metathesis catalyst.

These so-called (E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytyl-phenylester (=(E/Z)-2-phytyl-3,5,6-trimethylhydroquinone dialkanoate) and(E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytyl-phenyl silyl ether,respectively, are 2-phytyl-3,5,6-trimethylhydroquinone derivatives andsuitable precursors for α-tocopherol and x-tocopheryl alkanoatesrepresented by the formula V as shown in FIG. 1. The reaction of acompound of formula I with a compound of formula II is across-metathesis reaction. The compounds represented by formula VI (seeFIG. 1) are produced as byproducts. They can easily be removed by columnchromatography or distillation.

Concerning the substituent R¹: The term “C₂₋₅-alkanoyloxy” covers linearC₂₋₅-alkanoyloxy and branched C₄₋₅-alkanoyloxy. R¹ is preferablyacetyloxy or pivaloyloxy, more preferably it is acetyloxy.

Concerning the substituent R²: The expression “C₂₋₅-alkanoyloxy”incorporates linear C₂₋₅-alkanoyloxy and branched C₄₋₅-alkanoyloxy. Theterm C₁₋₆-alkyl encloses linear C₁₋₆-alkyl and branched C₃₋₆-alkyl.

Preferably R² is OSiR⁶R⁷R⁸, more preferably R² is OSiR⁶R⁷R⁸ with R⁶, R⁷and R⁸ being C₁₋₆-allyl, whereby the number of the C atoms of all threesubstituents R⁶, R⁷ and R⁸ together is at least 6. Most preferred R² isOSi^(t)BuMe₂ (Me=methyl, ^(t)Bu=tert-butyl), OSi^(i)Pr₃(^(i)Pr=iso-propyl) or OSiBu₃ (Bu=n-butyl).

Concerning the substituents R³ and R⁴: The expression “C₁₋₅-alkyl”embraces linear C₁₋₅-alkyl and branched C₃₋₅-alkyl. Preferably R³ and R⁴are independently from each other C₁₋₅-alkyl, more preferably they areboth identical C₁₋₅-alkyl, most preferably they are both methyl.

Concerning the substituent R⁵: The expression “C₂₋₅-alkanoyloxy”incorporates linear C₂₋₅-alkanoyloxy and branched C₄₋₅-alkanoyloxy andthe expression “C₁₋₅-alkoxy” covers linear C₁₋₅-alkoxy and branchedC₃₋₅-alkoxy.

R⁵ is preferably H or CH₂R⁹, wherein R⁹ is formyloxy, C₂₋₅-alkanoyloxy,benzoyloxy and OSiR⁶R⁷R⁸ as defined above. More preferably R⁵ is H orCH₂R⁹ with R⁹ being formyloxy, C₂₋₅-alkanoyloxy or benzoyloxy, mostpreferably R⁵ is H.

The Cross-Metathesis Catalyst

Preferably the cross-metathesis catalyst used in the process accordingto the invention is a ruthenium compound used in homogeneous catalysis.Homogeneous catalysis means that the reaction mixture is monophasicduring the catalyzed reaction.

More preferably the ruthenium compound is a ruthenium metal carbenecomplex possessing (a) ruthenium metal center(s), having an electroncount of 16 and being penta-coordinated or a ruthenium metal carbenecomplex possessing (a) ruthenium metal center(s), having an electroncount of 18 and being hexa-coordinated. Preferred is a ruthenium metalcarbene complex possessing a ruthenium metal center, having an electroncount of 16 and being penta-coordinated. It has to be kept in mind thatthese are the forms in which the catalysts are present before thereaction, so-called “precatalysts”. The real “ccatalytic” species isformed in situ during the reaction, of which the structure is not known.

“Penta-coordinated” in this context does not necessarily mean that thereare five ligands per Ru metal center in the complex. It is also possiblethat one ligand provides two coordination sites, i.e. that the complexcontains four ligands per Ru metal center. The same applies for the term“hexa-coordinated”. Hexa-coordinated Ru-complexes might contain five orsix ligands, one of the five ligands providing two coordination sites, aso-called bidentate ligand.

More preferred examples for such ruthenium compounds are the rutheniummetal carbene complexes represented by the following formulae VIIa, VIIband VIIc:

wherein R¹⁰ is an optionally single or multiple C₁₋₅-alkylated and/orC₁₋₅-alkoxylated phenyl,G is ethane-1,2-diyl, ethylene-1,2-diyl, cyclohexane-1,2-diyl or1,2-diphenylethane-1,2-diyl,L¹ is PR¹¹R¹²R¹³, wherein R¹¹, R¹² and R¹³ are independently from eachother C₁₋₈-alkyl, phenyl or tolyl,A is CH₂, C(H)aryl, C(H)R¹⁴, C═C(R⁴)₂, C═C(H)Si(R¹⁵)₃,C(H)—C(H)═C(R¹⁴)₂, C═C(H)(phenyl), C(H)—C(H)═C(phenyl)₂ orC═C═C(phenyl)₂,wherein “aryl” is an optionally single or multiple C₁₋₅-alkylated and/orhalo genated phenyl, R¹⁴ is C₁₋₄-alkyl, R¹⁵ is C₁₋₆-alkyl or phenyl,L² is L or L¹,L³ and L⁴ are independently from each other pyridyl or 3-halopyridyl,wherein halo signifies Br or C¹,R¹⁶ and R¹⁷ are both H or form together a fused benzene ring, and R¹⁸ isC₁₋₅-alkoxy.

Concerning the substituent R¹⁰: Preferred examples for an optionallysingle or multiple C₁₋₅-alkylated and/or C₁₋₅-alkoxylated phenyl arephenyl, 2,6-dimethylphenyl, 2,3,6-trimethylphenyl,2,4,6-trimethylphenyl, 2,6-dimethyl-4-methoxy-phenyl, 2-isopropylphenyl,2,6-diisopropylphenyl and 2-isopropyl-6-methylphenyl. More preferredexamples for R¹⁰ are 2,6-dimethylphenyl, 2,4,6-trimethylphenyl and2,6-diisopropylphenyl.

Concerning the substituent G: Preferably G is ethane-1,2-diyl.

Concerning the substituent L¹: The term “C₁₋₈-alkyl” includes linearC₁₋₈-alkyl, branched C₃₋₈-alkyl and C₅₋₈-cycloalkyl. Preferably L¹ isP(R¹¹)₃, wherein R¹¹ is linear C₁₋₈-alkyl, C₅₋₈-cycloalkyl or phenyl.More preferably L¹ is P(C₆H₁₁)₃ (“C₆H₁₁”=cyclohexyl), P(C₅H₉)₃(“C₅H₉”=cyclopentyl) or PPh₃ (“Ph”=phenyl).

Concerning the substituent A: The term “halogenated” means fluorinated,chlorinated or brominated, whereby chlorinated is preferred. Preferredexamples for an optionally single or multiple C₁₋₅-alkylated and/orhalogenated phenyl are phenyl, 4-chlorophenyl, 2,6-dimethylphenyl,2,3,6-trimethylphenyl, 2,4,6-trimethylphenyl,2,6-dimethyl-4-methoxyphenyl, 2-isopropylphenyl, 2,6-diisopropylphenyland 2-isopropyl-6-methylphenyl. The expression “C₁₋₄-alkyl” (substituentR¹⁴) includes linear C₁₋₄-alkyl as well as branched C₃₋₄-alkyl. Theexpression “C₁₋₆-alkyl” (substituent R¹⁵) includes linear C₁₋₆-alkyl aswell as branched C₃₋₆-alkyl.

Preferably A is C(H)CH₃, C(H)CH₂CH₃, C(H)(phenyl), C(H)(4-chlorophenyl),C═C(H)(phenyl), C═C(H)Si(CH₃)₃, C(H)—C(H)═C(Me)₂ andC(H)—C(H)═C(phenyl)₂. More preferably A is C(H) (phenyl),C(H)—C(H)═C(Me)₂ and C(H)—C(H)═C(phenyl)₂. Most preferably A isC(H)(phenyl).

Concerning the substituents L³ and L⁴: Preferably L³ and L⁴ are bothidentical. More preferably they are both 3-bromopyridyl.

Concerning the substituents R¹⁶ and R¹⁷: Preferably they are both H.

Concerning the substituent R¹⁸: The term “C₁₋₅-alkoxy” includes linearC₁₋₅-alkoxy as well as branched C₃₋₅-alkoxy. Preferably R¹⁸ isisopropoxy or methoxy, more preferably R¹⁸ is isopropoxy.

Preferred examples for complexes represented by the formula VIIa areillustrated in FIGS. 2 and 3. Preferred examples for complexesrepresented by the formula VIIb are illustrated in FIG. 4 (A is C(H)CH₃,C(H)CH₂CH₃, C(H)(phenyl), C(H)(4-chlorophenyl), C═C(H)(phenyl),C═C(H)Si(CH₃)₃, C(H)—C(H)═C(Me)₂ and C(H)—C(H)═C(phenyl)₂). Preferredexamples for complexes represented by the formula VIIc are illustratedin FIG. 5.

The most preferred cross-metathesis catalyst used in the processaccording to the invention is the following ruthenium metal carbenecomplex of formula VIII:

Synthesis of the Catalyst

The synthesis of the ruthenium carbene complexes represented by theformulae VIIa, VIIb, VIIc and VIII is e.g. described by P. Schwab, M. B.France, J. W. Ziller and R. H. Grubbs in Angew. Chem. Int. Ed. Engl.1995, 34(18), 2039-2041; by M. Scholl, S. Ding, C. W. Lee and R. H.Grubbs in Organic Letters 1999, 1(6), 953-956 (see especially footnote16); by S. B. Garber, J. S. Kingsbury, B. L. Gray and A. H. Hoveyda inJ. Am. Chem. Soc. 2000, 122, 8168-8179; by J. Huang, E. D. Stevens, S.P. Nolan and J. L. Petersen in J. Am. Chem. Soc. 1999, 121, 2674-2678(see especially page 2678); by M. Scholl, T. M. Trnka, J. P. Morgan andR. H. Grubbs in Tetrahedron. Lett. 1999, 40, 2247-2250 (see especiallynote 13); by S. T. Nguyen, L. K. Johnson and R. H. Grubbs in J. Am.Chem. Soc 1992, 114, 3974-3975 and the supplementary material thereto;by T. Opstal and F. Verpoort in Synlett 2003, 3, 314-320 (see especiallyreference 16); by M. S. Sanford, M. Ulman and R. H. Grubbs in J. Am.Chem. Soc. 2001, 123, 749-750 (see especially the supplementary materialthereto); by A. K. Chatterjee and R. H. Grubbs in Organic Letters 1999,1(11), 1751-1753; by A. K. Chatterjee, J. P. Morgan, M. Scholl and R. H.Grubbs in J. Am. Chem. Soc. 2000, 122, 3783-3784; and by J. P. Morganand R. H. Grubbs in Organic Letters 2000, 2(20), 3153-3155 (footnote13).

Synthesis of the Starting Material

2-Alkenyl-3,5,6-trimethylhydroquinone 1-acetate can be prepare d byO-alkylation of 2,3,6-trimethylhydroquinone 1-acetate followed by arearrangement analogous to the processes as e.g. described by Y. Tanada,K. Mori in Eur. J. Org. Chem. 2003, 848-854 (see especially scheme 5 andthe preparation of compound 19 on page 852 and 853); by J. C. Gilbert,M. Pinto in J. Org. Chem. 1992, 57, 5271-5276; in EP-A 0 345 593 (seeespecially reference examples 1 and 2 on page 6/7); or by N. Al-Maharik,N. G. Botting in Tetrahedron 2003, 59, 4177-4181 (see especially chapter3.1.2 and 3.1.3). The other 2-alkenyl-3,5,6-trimethylhydroquinone1-alkanoates can be prepared analogously or by a Friedel-Craftsalkylation (see example A).

The starting material for those, the 2,3,6-trimethylhydroquinone1-alkanoates (=4-alkanoyloxy-2,3,5-trimethylphenols) such as2,3,6-trimethylhydroquinone 1-acetate, may be obtained e.g. by selectivehydrolysis of the dialkanoates such as 2,3,5-trimethylhydroquinonediacetate as described in EP-A 1 239 045.

2,3,5-Trimethylhydroquinone diacetate can be prepared e.g. by the acidcatalyzed rearrangement of ketoisophorone in the presence of aceticanhydride or another acetylation agent as described in EP-A 0 850 910,EP-A 0 916 642, EP-A 0 952 137 or EP-A 1 028 103. The other alkanoatescan be prepared by acylation of TMHQ.

4-alkanoyloxy-2-alkenyl-3,5,6-trimethylphenyl silyl ethers, compoundsrepresented by the formula I with R²═OSiR⁶R⁷R⁸, can be prepared bysilylation of 2-alkenyl-3,5,6-trimethylhydroquinone 1-alkanoate withClSiR⁶R⁷R⁸ according to standard procedures for the silylation ofalkohols and as e.g. described by E. J. Corey and A. Venkateswarlu in J.Am. Chem. Soc. 1972, 94(17), 6190-6191.

2-Alkenyl-3,5,6-trimethylhydroquinone dialkanoates were synthesised byacylation of 2-Alkenyl-3,5,6-trimethylhydroquinone 1-alkanoate in thepresence of an acylating agent.

2,6,10,14-Tetramethylpentadecene may be obtained according to theprocedure disclosed of K. Sato, S. Mizuno, M. Hirayama in J. Org. Chem.1967, 32, 177-180 (see especially page 180).

The phytol derivatives, compounds b) represented by the formula II withR⁵═CH₂R⁹, can be produced by conventional processes for preparing phytylesters, phytyl silyl ethers and phytyl ethers known to the personskilled in the art. Processes for their manufacture are e.g. describedin EP-A 0 004 889 or in FR-A 2 627 384.

The 3-alkenyl-2,5,6-trimethylhydroquinone derivatives of formula I aswell as the phytol derivatives of formula II with R⁵═CH₂R⁹ can be usedas E/Z-mixture as well as in pure E- or pure Z-form. In both casespreferred is the use of the E/Z-mixtures, since the E/Z ratio of thesestarting materials is not maintained in the resulting product of formulaIII and the later following ring closure is independent from this ratio(see FIG. 1)

Cross-Metathesis Reaction

The catalysts, especially those represented by the formulae VIIa, VIIb,VIIc and VIII, which can be obtained e.g. according to the processesdescribed in the literature cited above or are also commerciallyavailable. Conveniently they are used as solution, whereby as solventthat solvent is used in which the reaction is carried out. Theconcentration of the solution is not critical. Conveniently theconcentration of the solution is from about 0.05 to about 2% by weight,preferably from about 0.1 to about 1% by weight, more preferably fromabout 0.4 to about 0.6% by weight, based on the total weight of thesolution. If the reaction is carried out essentially in the absence ofan additional solvent, the catalyst is used as such.

Conveniently the reaction is carried out in the absence or presence ofan aprotic organic solvent and essentially in the absence of water andprotic (in) organic solvents. “Essentially” in this context means thatthe amount of water, protic (in) organic solvents and additionalsolvent, respectively, is lower than 0.05 mol %, preferably lower than0.01 mol %, more preferably lower than 0.005 mol %-referred to the totalamount of solvent.

If the reaction is carried out in an additional aprotic organic solvent,especially dialkyl ethers R¹⁹—O—R²⁰, wherein R¹⁹ and R²⁰ areindependently from each other linear C₁₋₄-alkyl or branched C₃₋₈-alkyl,R¹⁹—O—R²⁰ preferably being methyl t-butyl ether, diethyl ether or2,2-dimethylpropyl methyl ether; tetrahydrofuran; tetrahydropyran;1,4-dioxane; methylene chloride; chloroform; cumene (=iso-propylbenzene)and an optionally once, twice or thrice methylated arylene such asbenzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, mesitylene,pseudocumene, hemellitene or mixtures thereof are used.

More preferably the aprotic organic solvent is tetrahydrofuran,methylene chloride, chloroform, toluene or a mixture thereof. The mostpreferred aprotic organic solvent is toluene.

The molar ratio of the compound a) of the formula I to the compound b)of the formula II in the reaction mixture conveniently varies from about1:10 to about 10:1, preferably from about 1:5 to about 5:1, morepreferably from about 1:3 to about 1:2.5. Most preferably compound b) isused in excess. If an excess of compound b) of formula II, 2,6,0,14-tetramethylpentadecene or a phytol derivative, is used,non-reacted material can be recycled after termination of the reactionand separation of the product by column chromatography. The same appliesif an excess of compound a) is used. In general also a mixture of thenon-reacted starting materials, compounds a) and b), can be recycled.

The amount of the cross-metathesis catalyst used, especially of theformulae VIIa, VIIb, VIIc and VIII, is based on the amount of compounda) or b), whichever is used in the lesser molar amount. Usually therelative amount of the catalyst to the amount of compound a) or b),whichever is used in the lesser molar amount, preferably to the amountof compound a) used in the lesser amount, is from about 0.0001 to about20 mol %, preferably from about 1.0 to about 10 mol %, more preferablyfrom about 2 to about 5 mol. %. In this context the expression “amountof catalyst” is to be understood as referring to the amount of the purecatalyst present, even though the catalyst may be impure and/or in theform of an adduct with a solvent.

The amount of the aprotic organic solvent used is conveniently fromabout 3 to about 15 ml, preferably from about 4 ml to about 10 ml, morepreferably from about 4.5 ml to 8 ml, based on 1 mmol of compound a) orb), whichever is used in the lesser amount.

The reaction temperature is dependent from the solvent/solvent mixtureused. Conveniently it ranges from about 10° C. to about 120° C.,preferably from about 30° C. to about 100° C., more preferably fromabout 40° C. to about 85° C.

The pressure under which the reaction is carried out is not critical,but dependent from the temperature and the solvent/solvent mixture used.The reaction is conveniently carried out at atmospheric pressure, butwhen solvents/solvent mixtures with a boiling point below the reactiontemperature are used, pressure must be applied. Essentially in theabsence of an additional solvent the reaction is carried out preferablyat reduced pressure, especially at a pressure below 100 mbar, a pressurebelow 40 mbar being even more preferred.

Moreover, the process is conveniently carried out under an inert gasatmosphere, preferably gaseous nitrogen or argon.

The process in accordance with the invention can be carried outbatchwise or continuously, and in general operationally in a very simplemanner, e.g. by adding a mixture of compounds a) and b)—as such ordissolved in the aprotic organic solvent such as mentioned above,preferably as solution—continuously to a mixture of the catalyst and theaprotic organic solvent.

After completion of the addition and an appropriate subsequent reactionperiod the isolation of the product and its purification if required,can be effected by procedures conventionally used in organic chemistry.

The present invention provides a new route to(E/Z)-2-phytyl-3,5,6-trimethylhydroquinone dialkanoate,(E/Z)-4-alkanoyloxy-3,5,6-trimethyl-2-phytyl-phenyl silyl ether(compounds of formula III), α-tocopherol and α-tocopheryl alkanoates(compounds of formula V, wherein R²¹ is OH and C₂₋₅-alkanoyloxy,respectively) (see FIG. 1). This process has the advantage of avoidingthe production of benzofurans/phytadienes, formed during conventionalsynthesis of α-tocopherol and its derivatives and difficult to removefrom the product. A further advantage of the process in accordance withthe invention is, in addition to the work at lower temperatures comparedwith conventional α-tocopherol (alkanoate) production processes, theavoidance of corrosion.

Another aspect of the present invention is a process for the manufactureof α-tocopherol and α-tocopheryl alkanoates represented by the followingformula V

comprising the following steps:

-   -   i) reacting of a compound represented by the following formula I    -   with a compound represented by the following formula II    -   to a compound represented by the following formula III    -   in the presence of a cross-metathesis catalyst,    -   ii) converting the compound represented by the formula III and        obtained in step i) to        (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone (R²¹═OH) or a        (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone 1-alkanoate        (R²¹═C₂₋₅-alkanoyloxy) represented by the following formula IV,        and    -   iii) subjecting the compound represented by the formula IV and        obtained in step ii) to a cyclization to α-tocopherol (R²¹═OH)        or an α-tocopheryl alkanoate (R²═C₂₋₅-alkanoyloxy) represented        by the formula V,        wherein R¹, R², R³, R⁴ and R⁵ are as defined above, and R²¹ is        OH or R¹.

While the production of (all-rac)-α-tocopheryl alkanoates and(all-rac)-α-tocopherol is preferred, the invention is not limited to theproduction of those particular isomeric forms and other isomeric formscan be obtained by using 2,6,10,14-tetramethylpentadecene or a phytolderivative as the starting material in the appropriate isomeric form.Thus, (RS,R,R)α-tocopheryl alkanoate and (RS,R,R)-α-tocopherol will beobtained when using (R,R)-2,6,10,14-tetramethylpentadecene or a(R,R)-phytol derivative as starting material.

Step i) is carried out as described above. The steps ii) and iii) arefurther described in more detail in the following.

Step ii)

Step ii) is depending on the substituent R² of compound III. If R² isOSiR⁶R⁷R⁸ as defined above and R¹ is C₂₋₅-alkanoyloxy, the silyl ethermight be selectively cleaved in presence of the ester to yield(E/Z)-3-phytyl-2,5,6-trimethylhydroquinone 1-alkanoate. The cleavage ofsilylethers is e.g. carried out as described by S. V. Ankala and G.Fenteany in Tetrahedron Lett. 2002, 43, 4729-4732.

If R¹ and R² are both C₂₋₅-alkanoyloxy, both ester groups are cleavedunder acidic or basic conditions or by hydrogenolysis or as e.g.described by C. Ramesh, G. Mahender, N. Ravindranath and B. Das inTetrahedron 2003, 59, 1049-1054 and the references cited therein. Thethus obtained (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone (formula IVwith R²═OH) can be used in step iii) to obtain α-tocopherol.

Step iii)

The ring closure of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone and(E/Z)-3-phytyl-2,5,6-trimethylhydroquinone 1-alkanoate, respectively, inaccordance with the invention can be effected by their treating with anacid catalyst in the presence or absence of a solvent accordingto/analogous to the procedure described in WO 03/37883 for the ringclosure of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone. The content of WO03/37883 is incorporated herein.

Advantageously the thus obtained α-tocopherol (formula V with R²¹═OH) istransferred into its alkanoate (formula V with R²¹═C₂₋₅-alkanoyloxy) byacylation as e.g. described in U.S. Pat. No. 2,723,278 and U.S. Pat. No.6,444,098, since the alkanoates are more stable than α-tocopherolitself. Therefore the process where compounds of formula I withR²═OSiR⁶R⁷R⁸, wherein R⁶, R⁷ and R⁸ are as defined above, are used ispreferred, since it produces the more stable α-tocopheryl alkanoates via(E/Z)-3-phytyl-2,5,6-trimethylhydroquinone 1-alkanoates.

The following examples illustrate the invention in more detail, but arenot intended to limit its scope in any way.

EXAMPLES

The structure of the products was confirmed with ¹H nuclear magneticresonance spectroscopy (¹H NMR), mass spectroscopy (MS), infraredspectroscopy (IR) and elemental analysis. Their purity was checked withgas chromatography (GC).

Examples A-I Synthesis of the Starting Material Example A Synthesis of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone 1-acetate

A 1.5 l european-style three neck flask, equipped with a mechanicalstirrer, a connection to inert gas and a 50 ml dropping funnel wascharged with 515 mmol (100 g) of 2,3,6-trimethylhydroquinone 1-acetate,670 mmol (57.7 g; 70 ml) of 3-methyl-butene-3-ol and 1 l of methylenechloride and cooled in an icebath to 0° C. and flushed with argon. Thedropping funnel was charged with ca. 260 mmol (32.5 ml) of BF₃.Et₂O(˜48%; Fluka, product number: 15720). This solution was added dropwiseunder stirring and ice cooling during 2 hours. After another 30 min thereaction mixture was poured on 1 liter of an aqueous 5% by weight sodiumbicarbonate solution and stirred for 1 hour at 22° C. The organic phasewas separated, washed neutral with an aqueous 5% by weight sodiumbicarbonate solution and brine. The aqueous phases were extracted twicewith 200 ml of methylene chloride. The combined organic phases weredried over sodium sulfate, filtered and concentrated in vacuo to give146.4 g of a crude product. Recristallisation from 250 ml of boilingn-hexane gave 95.3 g of a white cristalline product of 97.7% purity (GCarea) melting at 110° C. The yield is 69%-based on2,3,6-trimethylhydroquinone 1-acetate.

Example B Synthesis of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate

(Formula I with R¹═R²═OC(O)CH₃, R³═R⁴═CH₃)

3-(3′-Methyl-2′-butenyl)-2,5,6-trimethylhydroquinone 1-acetate isacetylated with acetic anhydride in the presence of catalytic amounts ofN,N-dimethylaminopyridine according to standard procedures known to theperson skilled in the art to give3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate.

Example C Synthesis of4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyl tributylsilylether

(formula I with R¹═OC(O)CH₃, R²═OSiBu₃, R³═R⁴═CH₃)

A schlenk tube equipped with a magnetic stirrer and placed under argonwas charged with 2.0 mmol (515 mg) of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone 1-acetate and 6 mLof dry tetrahydrofurane. To this solution were added dropwise viasyringes successively 2.0 mmol (280 μL) of triethylamine and 2.0 mmol(335 μL) of n-tributylchlorosilane. The resulting solution was heated to50° C. while a white precipitate was rapidly formed. After 18 hours at50° C. the solvent was evaporated in vacuo and the crude product waspurified by column chromatography over silica gel using a mixture ofdiethylether and hexane (v/v=1:9) as eluent. 11.0 mmol (510 mg) of4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyl tributylsilylether were isolated as a colorless oil (yield: 55% based on3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone 1-acetate, purity:99.3%-GC area).

Example D Synthesis of4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether

(formula I with R¹═OC(O)CH₃, R²═OSiMe₂ ^(t)Bu, R³═R⁴═CH₃)

A schlenk tube equipped with a magnetic stirrer and a placed under argonwas charged with 5.0 mmol (1.31 g) of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone 1-acetate, 7.1 mmol(1.13 g) of tert-butyldimethylchlorosilane, 15.0 mmol (1.02 g) ofimidazole and 5 mL of dry dimethylformamide (DMF). The yellow solutionwas stirred at 22-23° C. during 16 hours. Then, 40 mL of diethyletherand 15 ml of an aqueous solution of HCl (10% by weight) were added andthe organic phase was extracted thrice with 15 mL of diethylether. Thecombined organic phases were washed with 30 mL of a saturated aqueoussolution of NaHCO₃ and dried over Na₂SO₄. After filtration, the solventwas removed in vacuo to afford an oil which was purified by columnchromatography over silica gel using a mixture of diethylether andhexane (v/v=1:4) as eluent. 4.9 mmol (1.84 g) of4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether were isolated as a slightly yellow oilwhich solidified upon standing at 22-23° C. (yield: 98% based on3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone 1-acetate, purity:99.6%-GC area).

Example E Synthesis of 2,6,10,14-tetramethylpentadecene

(Formula II with R⁵═H)

A flask, equipped with a mechanical stirrer and placed under argon, wascharged with 1.80 mol (642.6 g) of triphenylmethylphosphonium bromideand 2 L of tetrahydrofurane (THF). To this suspension 1.88 mol (1.175 L)of a solution of butyllithium (1.6 mol/L in hexane) were added dropwiseduring 3 hours at 0° C. The resulting mixture was stirred at 0° C. foran additional hour. Then 1.50 mol (402.7 g) of6,10,14-trimethyl-2-pentadecanone were added dropwise at 0° C. during 1hour and the mixture was allowed to warm up to 22 to 23° C. After 2hours, 150 mL of water were added dropwise and the resulting whitesuspension was filtered off over decalite. The filtrate was washedthrice with 300 mL of water and dried over Na₂SO₄. After filtration andevaporation of the solvent in vacao, the mixture was filtered off overdecalite to remove white cristals and the filtrate was evaporated invacuo. The resulting crude oil was purified by distillation under vacuum(145° C., 0.2 mbar) to give 1.20 mol (319.2 g) of2,6,10,14-tetramethylpentadecene as a colorless oil (yield: 80% based on6,10,14-trimethyl-2-pentadecanone; purity: 96.2%-GC area).

Example F Synthesis of (E/Z)-(all-rac)-phytyl acetate

(Formula II with R⁵═CH₂OC(O)CH₃)

A mixture of 20 mmol (6.23 g) of (E/Z)-(all-rac)-phytol (E/Zratio=72/28), 25 mmol (1.98 g) of pyridine, 20 mmol (2.04 g) of aceticanhydride and 5 mL of n-hexane was stirred at 21 to 22° C. for 16 to 18hours. 30 mL of water were added and the resulting mixture was extractedthrice with 50 mL of diethyl ether. The organic phases were combined andwashed thrice with 30 mL of aqueous HCl (10% by weight), neutralisedwith 50 mL of a saturated solution of NaHCO₃, washed with 50 mL of asaturated solution of NaCl and with 50 mL of water and dried overNa₂SO₄. After filtration, the solvent was removed in vacuo to afford acolorless oil which was purified by column chromatography over silicagel using a mixture of diethylether and hexane (v/v=1:4) as eluent. 5.62g (16.6 mmol) of (all-rac)-Phytyl acetate were obtained as a colorlessoil with an E/Z ratio of 2.5 (yield: 83% based on (all-rac)-phytol,purity: 98.2%-GC area).

Example G Synthesis of (E)-(R,R)-phytyl acetate

Example F was repeated, but instead of (all-rac)-phytol (E)-(RR)-phytol(E/Z=99.7/0.3) was used. (E)-(R,R)-phytyl acetate (purity: 96.5%-GCarea); E/Z=99.6/0.4) was obtained in a yield of 60.5%.

Example H Synthesis of (E,Z)-(all-rac)-phytyl formiate (according toEP-A 0 004 889)

(formula II with R⁵═CH₂OC(O)H)

A mixture of 10 mmol (3.11 g) of (E,Z)-(all-rac)-phytol (E/Z=72/28) and100 mmol (4.60 g) of formic acid was vigorously stirred at 60° C. for2.5 hours. Then 30 mL of water were added to the mixture and the organicphase was extracted twice with 30 mL of diethyl ether. The combinedorganic phases were dried over Na₂SO₄ and after filtration, the solventwas removed in vacuo to afford a yellow oil. This oil was was purifiedby column chromatography over silica gel using a mixture of diethyletherand hexane (v/v=5:95) as eluent. 9.0 mmol (2.92 g) of(E,Z)-(all-rac)-phytyl formiate were obtained as a colorless oil(E/Z=65/35; yield: 90% based on (all-rac)-phytol).

Example I Synthesis of (E,Z)-(all-rac)-phytyl benzoate

(formula II with R⁵═CH₂OC(O)(phenyl))

A mixture of 48.6 mmol (15.02 g) of (E,Z)-(all-rac)-phytol (E/Z=72/28),51.1 mmol (11.56 g) of benzoic anhydride and 2.4 mmol (0.30 g) ofN,N-dimethylaminopyridine in 30 mL of hexane was stirred at 23 to 24° C.for 20 hours. Then 50 ml of water were added and the organic phase wasextracted thrice with 50 mL of diethyl ether. The combined organicphases were washed thrice with an aqueous solution of HCl (10% byweight), neutralised with 50 mL of a saturated solution of NaHCO₃,washed with 50 mL of a saturated solution of NaCl and with 50 mL ofwater and dried over Na₂SO₄. After filtration, the solvent wasevaporated in vacuo to afford a colorless oil and a white precipitate.This crude material was purified by column chromatography over silicagel using a mixture of ethyl acetate and hexane (v/v=5:95) as eluent.37.2 mmol (14.80 g) of (E,Z)-(all-rac)-phytyl benzoate were isolated asa colorless oil (E/Z=68/32; yield: 76% based on (all-rac)-phytol;purity: 99.5%-GC area).

Examples J-U Synthesis of (E/L)-3-phytyl-2,5,6-trimethylydroquinonederivatives

In the following examples complex VIII was used as catalyst for thecross-metathesis reactions. The results of the cross-metathesisreactions are summarized in table 1. TABLE 1 Results of thecross-metathesis reactions (examples J-S) E/Z ratio of the ExampleStarting material product yield product J 3-(3′-methyl-2′-butenyl)-(E/Z)-3-phytyl-2,5,6- 69% 2.5 2,5,6-trimethylhydroquinonetrimethylhydroquinone diacetate + 2,6,10,14- diacetatetetramethylpentadecene K 3-(3′-methyl-2′-butenyl)- (E/Z)-3-phytyl-2,5,6-60% 2.3 2,5,6-trimethylhydroquinone trimethylhydroquinone diacetate +2,6,10,14- diacetate tetramethylpentadecene in vacuo L3-(3′-methyl-2′-butenyl)- (E/Z)-3-phytyl-2,5,6- 46% 2.12,5,6-trimethylhydroquinone trimethylhydroquinone diacetate +(E/Z)-(all-rac)- diacetate phytyl acetate M 3-(3′-methyl-2′-butenyl)-(E/Z)-3-phytyl-2,5,6- 50% 2.0 2,5,6-trimethylhydroquinonetrimethylhydroquinone diacetate + (E/Z)-(all-rac)- diacetate phytylbenzoate N 4-acetyloxy-2-(3′-methyl-2′- (E/Z)-4-acetyloxy-2- 60% 2.8butenyl)-3,5,6-trimethylphenyl phytyl-3,5,6- tributylsilyl ether +2,6,10,14- trimethylphenyl tributyl- tetramethylpentadecene silyl etherO 4-acetyloxy-2-(3′-methyl-2′- (E/Z)-4-acetyloxy-2- 70% 2.7butenyl)-3,5,6-trimethylphenyl phytyl-3,5,6- tert-butyldimethylsilylether + trimethylphenyl tert- 2,6,10,14-tetramethylpentadecenebutyldimethylsilyl ether P 4-acetyloxy-2-(3′-methyl-2′-(E/Z)-4-acetyloxy-2- 56% 2.6 butenyl)-3,5,6-trimethylphenylphytyl-3,5,6- tert-butyldimethylsilyl ether + trimethylphenyl tert-2,6,10,14-tetramethylpentadecene butyldimethylsilyl ether in vacuo Q4-acetyloxy-2-(3′-methyl-2′- (E/Z)-4-acetyloxy-2- 52% 2.1butenyl)-3,5,6-trimethylphenyl phytyl-3,5,6- tert-butyldimethylsilylether + trimethylphenyl tert- (E/Z)-(all-rac)-phytyl acetatebutyldimethylsilyl ether R 4-acetyloxy-2-(3′-methyl-2′-(E/Z)-4-acetyloxy-2- 54% 1.9 butenyl)-3,5,6-trimethylphenylphytyl-3,5,6- tert-butyldimethylsilyl ether + trimethylphenyl tert-(E)-(R,R)-phytyl acetate butyldimethylsilyl ether S(E/Z)-4-acetyloxy-2-(3′- (E/Z)-4-acetyloxy-2- 42% 2.1methyl-2′-butenyl)-3,5,6- phytyl-3,5,6- trimethylphenyl tert-trimethylphenyl tert- butyldimethylsilyl ether + butyldimethylsilylether (E/Z)-(all-rac)-phytyl formiate

Example J Synthesis of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinonediacetate starting from3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate and2,6,10,14-tetramethylpentadecene

A schlenk tube, placed under argon and equipped with a magnetic stirrer,was charged with 0.01 mmol (8.4 mg) of the catalyst, 0.2 mmol (36.8 mg)of tridecane and 2 mL of toluene. To this solution, a mixture of 0.2mmol (60.8 mg) of 3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinonediacetate and 0.4 mmol (107 mg) of 2,6,10,14-tetramethylpentadecenedissolved in 4 mL of toluene was added at 21 to 22° C. The resultingbrown solution was stirred at 21 to 22° C. for 10 minutes and then at80° C. for 18 hours. The progress of the reaction can be monitored byGC. After 18 hours the meanwhile orange solution was cooled to 21 to 22°C. and reduced in vacuo to afford a brown oil which was purified bycolumn chromatography over silica gel using a mixture of diethyletherand hexane (v/v=1:4) as eluent. 0.14 mmol (71 mg) of(E/Z)-3-phytyl-2,5,6-trimethylhydroquinone diacetate were isolated as acolorless oil with a E/Z ratio of 2.5 (determined by ¹H NMR) (yield: 69%based on 3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinonediacetate).

Example K Synthesis of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinonediacetate starting from3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate and2,6,10,14-tetramethylpentadecene in vacuo

A mixture of 0.8 mmol of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate, 1.6 mmolof 2,6,10,14-tetramethylpentadecene and 0.04 mmol of the catalyst wasvigorously stirred at 80° C. for 3 hours in vacuo (33 mbar). The yieldwas 60% based on 3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinonediacetate. The E/Z ratio of the product,(E/Z)-3-phytyl-2,5,6-trimethylhydroquinone diacetate, was 2.3(determined by ¹H NMR).

Example L Synthesis of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinonediacetate starting from3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroguinone diacetate and(E/Z)-(all-rac)-phytyl acetate

Example J was repeated under the same conditions except that 0.4 mmol of(E/Z)-(all-rac)-phytyl acetate were used instead of 0.4 mmol of2,6,10,14-tetramethylpentadecene. The yield was 46% based on3-(3′-methyl-2′-butenyl-2,5,6-trimethylhydroquinone diacetate. The E/Zratio of the product, (E/Z)-3-phytyl-2,5,6-trimethylhydroquinonediacetate, was 2.1 (determined by ¹H NMR).

Example M Synthesis of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinonediacetate starting from3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate and(E/Z)-(all-rac)-phytyl benzoate

Example J was repeated under the same conditions except that 0.4 mmol of(E/Z)-(all-rac)-phytyl benzoate were used instead of 0.4 mmol of2,6,10,14-tetramethylpentadecene. The yield was 50% based on3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate. The E/Zratio of the product, (E/Z)-3-phytyl-2,5,6-trimethylhydroquinonediacetate, was 2.0 (determined by ¹H NMR).

Example N Synthesis of (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltributylsilyl ether starting from4-acetyloxy-2(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyl tributylsilylether and 2,6,10,14-tetramethylpentadecene

Example J was repeated under the same conditions except that 0.2 mmol or4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyl tributylsilylether were used instead of 0.2 mmol of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate. Theyield was 60% based on4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyl tributylsilylether. The E/Z ratio of the product,(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tributylsilyl ether,was 2.8 (determined by GC).

Example O Synthesis of (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltert-butyldimethylsilyl ether starting from4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether and 2,6,10,14-tetramethylpentadecene

Example J was repeated under the same conditions except that 0.2 mmol of4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether were used instead of 0.2 mmol of3-(3′-methyl-2′-butenyl)-2,5,6-trimethylhydroquinone diacetate. Theyield was 70% based on4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether. The E/Z ratio of the product,(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether, was 2.7 (determined by GC).

Example P Synthesis of (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltert-butyldimethylsilyl ether starting from4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether and 2,6,10,14-tetramethylpentadecene invacuo

A mixture of 0.4 mmol of4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether, 0.8 mmol of2,6,10,14-tetramethylpentadecene and 0.02 mmol of the catalyst wasvigorously stirred at 80° C. for 3 hours in vacuo (33 mbar). The yieldwas 56% based on4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether. The E/Z ratio of the product,(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether, was 2.6 (determined by GC).

Example O Synthesis of (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltert-butyldimethylsilyl ether starting from4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether and (E/Z)-(all-rac)-phytyl acetate

Example O was repeated under the same conditions except that 0.4 mmol of(E/Z)-(all-rac)-phytyl acetate were used instead of 0.4 mmol of2,6,10,14-tetramethylpentadecene. The yield was 52% based on4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether. The E/Z ratio of the product,(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether, was 2.1 (determined by GC).

Example R Synthesis of (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltert-butyldimethylsilyl ether starting from4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether and (E)-(R,R)-phytyl acetate

Example O was repeated under the same conditions except that 0.4 mmol of(E)-(R,R)-phytyl acetate were used instead of 0.4 mmol of2,6,10,14-tetramethylpentadecene. The yield was 54% based on4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether. The E/Z ratio of the product,(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether, was 1.9 (determined by GC).

Example S Synthesis of (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltert-butyldimethylsilyl ether starting from(E/Z)-4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether and (E/Z)-(all-rac)-phytyl formiate

Example O was repeated under the same conditions except that 0.4 mmol of(E)-(all-rac)-phytyl formiate were used instead of 0.4 mmol of2,6,10,14-tetramethylpentadecene. The yield was 42% based on4-acetyloxy-2-(3′-methyl-2′-butenyl)-3,5,6-trimethylphenyltert-butyldimethylsilyl ether. The E/Z ratio of the product,(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether, was 2.1 (determined by GC).

Example T Synthesis of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone1-acetate starting from (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltert-butyldimethylsilyl ether

(See S. V. Ankala, G. Fenteany, Tetrahedron Lett. 2002, 43, 4729-4732.)

A mixture of 0.100 mmol (59.0 mg) of(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether (E/Z=2.1) and 0.359 mmol (15.0 mg) of LiOH.H₂O in 0.2 mL ofdimethylformamide was vigorously stirred at 22-23° C. during 16 hours.Then, the solvent was removed in vacuo and the crude oil was purified bycolumn chromatography over silica gel using a mixture of diethyletherand hexane (v/v=1:4) as eluent 0.066 mmol (31.2 mg) of(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether were isolated as a colorless oil with an E/Z ratio of 2.1(determined by GC) (yield: 66%-based on(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tert-butyldimethylsilylether).

Example U Synthesis of (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone1-acetate starting from (E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyltributylsilyl ether

(See S. V. Ankala, G. Fenteany, Tetrahedron Lett. 2002, 43, 4729-4732.)

A mixture of 0.074 mmol (50.0 mg) of(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tributylsilyl ether(E/Z=2.7) and 0.223 mmol (9.4 mg) of LiOH.H₂O in 0.2 mL ofdimethylformamide was vigorously stirred at 22-23° C. during 16 hours.Then, the solvent was removed in vacuo and the crude oil was purified bycolumn chromatography over silica gel using a mixture of diethyletherand hexane (v/v=1:4) as eluent. 0-055 mmol (26.1 mg) of(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tributylsilylether-were isolated as a colorless oil with an E/Z ratio of 2.5(determined by GC) (yield: 74%-based on(E/Z)-4-acetyloxy-2-phytyl-3,5,6-trimethylphenyl tributylsilyl ether).

1. A process for the manufacture of compounds represented by thefollowing formula III

wherein R¹ is C₂₋₅-alkanoyloxy, and R² is C₂₋₅-alkanoyloxy or OSiR⁶R⁷R⁸,and wherein R⁶, R⁷ and R⁸ are independently from each other C₁₋₆-alkylor phenyl, by the reaction of a) a compound represented by the followingformula I

wherein R¹ and R² are as defined above, and wherein R³ and R⁴ areindependently from each other H or C₁₋₅-alkyl, with the proviso that atleast one of R³ and R⁴ is not H, with b) a compound represented by thefollowing formula II

wherein R⁵ is H or CH₂—R⁹, wherein R⁹ is formyloxy, C₂₋₅-alkanoyloxy,benzoyloxy, C₁₋₅-alkoxy or OSiR⁶R⁷R⁸ as defined above, in the presenceof a cross-metathesis catalyst.
 2. The process as claimed in claim 1,wherein the cross-metathesis catalyst is a ruthenium compound used inhomogeneous catalysis.
 3. The process as claimed in claim 2, wherein theruthenium compound is a ruthenium metal carbene complex possessing (a)ruthenium metal center(s), having an electron count of 16 and beingpenta-coordinated or a ruthenium metal carbene complex possessing (a)ruthenium metal center(s), having an electron count of 18 and beinghexa-coordinated, preferably a ruthenium metal carbene complexpossessing a ruthenium metal center, having an electron count of 16 andbeing penta-coordinated.
 4. The process as claimed in claim 2, whereinthe ruthenium compound is one of the complexes represented by thefollowing formulae VIIa, VIIb and VIIc:

wherein R¹⁰ is an optionally single or multiple C₁₋₅-alkylated and/orC₁₋₅-alkoxylated phenyl, G is ethane-1,2-diyl, ethylene-1,2-diyl,cyclohexane-1,2-diyl or 1,2-diphenylethane-1,2-diyl, L¹ is PR¹¹R¹²R¹³,wherein R¹¹, R¹² and R¹³ are independently from each other C₁₋₈-alkyl,phenyl or tolyl, A is CH₂, C(H)aryl, C(H)R⁴, C═C(R⁴)₂, C═C(H)Si(R⁵)₃,C(H)—C(H)═C(R¹⁴)₂, C═C(H)(phenyl), C(H)—C(H)═C(phenyl)₂ orC═C═C(phenyl)₂, wherein “aryl” is an optionally single or multipleC₁₋₅-alkylated and/or halogenated phenyl, R¹⁴ is C₁₋₄-alkyl, R¹⁵ isC₁₋₆-alkyl or phenyl, L² is L or L: L³ and L⁴ are independently fromeach other pyridyl or 3-halopyridyl, wherein halo is Br or C¹, R¹⁶ andR¹⁷ are both H or form together a fused benzene ring, and R¹⁸ isC₁₋₅-alkoxy.
 5. The process as claimed in claim 2, wherein the rutheniumcompound is represented by the following formula VIII


6. The process as claimed in claim 1, wherein the reaction is carriedout in an aprotic organic solvent.
 7. The process as claimed in claim 6,wherein the aprotic organic solvent is a dialkyl ether R¹⁹—O—R²⁰,tetrahydrofuran, tetrahydropyran, 1,4-dioxane, methylene chloride,chloroform, cumene, an optionally once, twice or thrice methylatedarylene, or a mixture thereof, wherein R¹⁹ and R²⁰ are independentlyfrom each other linear C₁₋₄-alkyl or branched C₃₋₈-alkyl.
 8. The processas claimed in claim 7, wherein the aprotic organic solvent istetrahydrofuran, methylene chloride, chloroform, toluene or a mixturethereof, preferably toluene.
 9. The process as claimed in claim 6,wherein from about 3 ml to about 15 ml, preferably from about 4 ml toabout 10 ml, more preferably from about 4.5 ml to about 8 ml of theaprotic organic solvent are used per mmol of compound a) or b),whichever is used in the lesser amount.
 10. The process as claimed inclaim 1, wherein the reaction is carried out essentially in the absenceof an additional solvent.
 11. The process as claimed in claim 10,wherein the reaction is carried out in vacuo, preferably at a pressurebelow 100 mbar.
 12. The process as claimed in claim 1, wherein therelative amount of the cross-metathesis catalyst to the amount ofcompound a) or b), whichever is used in the lesser amount, is from about0.0001 mol % to about 20 mol %, preferably from about 1.0 mol % to about10 mol %, more preferably from about 2 to about 5 mol %.
 13. The processaccording to claim 1, wherein the molar ratio of compound a) to compoundb) present in the reaction mixture is from about 1:10 to about 10:1,preferably from about 1:5 to about 5:1, more preferably from about 1:3to about 1:2.5.
 14. The process as claimed in claim 1 wherein thereaction is carried out at temperatures from about 10° C. to about 120°C., preferably from about 30° C. to about 100° C., especially from about40° C. to about 85° C.
 15. A process for the manufacture of α-tocopheroland α-tocopheryl alkanoates represented by the following formula V

comprising the following steps: i) reacting of a compound represented bythe following formula I

with a compound represented by the following formula II

to a compound represented by the following formula III

in the presence of a cross-metathesis catalyst, ii) converting thecompound represented by the formula III and obtained in step i) to(E/2)-3-phytyl-2,5,6-trimethylhydroquinone or a(E/Z)-3-phylyl-2,5,6-trimethylhydroquinone 1-alkanoate represented bythe following formula IV, and

iii) subjecting the (E/Z)-3-phytyl-2,5,6-trimethylhydroquinone or(E/Z)-3-phytyl-2,5,6-trimethylhydroquinone 1-alkanoate represented bythe formula IV and obtained in step ii) to a cyclization to α-tocopherolor an α-tocopheryl alkanoate represented by the formula V, wherein R¹,R², R³, R⁴ and R⁵ are as defined in claim 1, and R²¹ is R¹ or OH. 16.Compounds of the formula III

wherein R¹ is C₂₋₅-alkanoyloxy, and R² is C₂₋₅-alkanoyloxy or OSiR⁶R⁷R⁸,and wherein R⁶, R⁷ and R⁸ are independently from each other C₁₋₆-alkylor phenyl.
 17. Compounds of the formula IX

wherein R²² is C₃₋₅-alkanoyloxy, and R²³ is C₃₋₅-alkanoyloxy orOSiR⁶R⁷R⁸, and wherein R⁶, R⁷ and R⁸ are independently from each otherC₁₋₆-alkyl or phenyl.
 18. Compounds of the formula X

wherein R¹ is C₂₋₅-alkanoyloxy.
 19. Compounds of the formula XI

wherein R²⁴ is C₃₋₅-alkanoyloxy.